The renin-angiotensine system (RAS) is a proteolytic cascade playing a fundamental role in regulating blood pressure and is apparently involved in the onset and maintenance of some cardiovascular pathologies, such as hypertension or heart failure.
The octapeptide hormone angiotensine II (AII) final product of RAS, is mainly formed in blood by the degradation of angiotensine I by the ACE enzyme which is localized in the endothelium of blood vessels, lungs, kidneys and many other organs. This hormone exerts on the arteries a powerful vasoconstrictive action as a consequence of its interaction with specific receptors, present on the cell membranes.
One of the possible control modes of RAS is the AII antagonism at the receptorial level. Some peptide analogues of AII (e.g. saralasine, sarmesine) are known to antagonize competitively the interactions of the hormone, but their clinical or experimental use has been limited by a partial agonist activity and by the lack of oral activity.
Recently, several non-peptide 5-or 6-membered heterocyclic compounds were disclosed as AII receptor antagonists. Example of these compounds are claimed in EP 253310, EP 323841, EP 324377, EP 409332, EP 411507, EP 412594 A, EP 419048 A.